Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function

Endothelial cells can convert L-citrulline to L-arginine, the precursor of nitric oxide. The present study tests the hypothesis that a C-to-A nucleotide transversion (T1405N) in the gene-encoding carbamoyl-phosphate synthetase 1, the enzyme catalyzing the rate-limiting step in L-citrulline formation, influences nitric oxide metabolite concentrations or nitric oxide-mediated vasodilation in humans. Bradykinin ( 100, 200, and 400 ng/min) was infused via brachial artery in 106 (CC: AC: AA = 40: 54: 12) healthy subjects. Sodium nitroprusside (1.6, 3.2, and 6.4 mug/min) was also infused in 87 (CC: AC: AA = 31: 46: 10) subjects. Forearm blood flow was measured by plethysmography and blood samples were collected for tissue-type plasminogen activator antigen, nitric oxide metabolites, and cyclic GMP. There was a significant relationship between carbamoyl-phosphate synthetase 1 genotype and nitric oxide metabolites, such that nitric oxide metabolite concentrations were highest in individuals homozygous for the C allele ( mean +/- SD, 14.0 +/- 8.5 mumol/L), lowest in individuals homozygous for the A allele (9.1 +/- 3.1 mumol/L), and intermediate (11.8 +/- 6.6 mumol/L) in heterozygotes (P = 0.036). There was a significant effect of carbamoyl-phosphate synthetase 1 genotype on forearm blood flow during bradykinin ( P = 0.028), such that the vasodilator response was greatest in C allele homozygotes (22.2 +/- 9.1 mL/min/100 mL at 400 ng/min), least in A allele homozygotes (13.6 +/- 6.2 mL/min/ 100 mL), and intermediate (19.4 +/- 10.7 mL/min/100 mL) in heterozygotes. Similarly, carbamoyl-phosphate synthetase 1 genotype influenced forearm blood flow during nitroprusside ( maximal flow 19.2 +/- 8.3, 18.1 +/- 8.3, and 11.5 +/- 4.9 mL/min/100 mL in the CC: AC: AA groups, respectively; P = 0.022). In contrast, there was no effect of carbamoyl-phosphate synthetase 1 genotype on the nitric oxide - independent tissue-type plasminogen activator response to bradykinin ( P = 0.943). These data indicate that a polymorphism in the gene encoding carbamoyl-phosphate synthetase 1 influences nitric oxide production as well as vascular smooth muscle reactivity.